Clonal expansion is a core aspect of T cell immunity. However, little is known with respect to the relationship between replicative history and the formation of distinct CD8⁺ memory T cell subgroups. To address this issue, we developed a genetic-tracing approach, termed the DivisionRecorder, that reports the extent of past proliferation of cell pools in vivo. Using this system to genetically ‘record’ the replicative history of different CD8⁺ T cell populations throughout a pathogen-specific immune response, we demonstrate that the central memory T (T_CM) cell pool is marked by a higher number of prior divisions than the effector memory T cell pool, owing to the combination of strong proliferative activity during the acute immune response and selective proliferative activity after pathogen clearance. Furthermore, by combining DivisionRecorder analysis with single-cell transcriptomics and functional experiments, we show that replicative history identifies distinct cell pools within the T_CM compartment. Specifically, we demonstrate that lowly divided T_CM cells display enriched expression of stem-cell-associated genes, exist in a relatively quiescent state, and are superior in eliciting a proliferative recall response upon activation. These data provide the first evidence that a stem-cell-like memory T cell pool that reconstitutes the CD8⁺ T cell effector pool upon reinfection is marked by prior quiescence.

克隆扩增是 T 细胞免疫的核心方面。^{然而，关于复制历史与不同 CD8 +}记忆 T 细胞亚群形成之间的关系知之甚少。为了解决这个问题，我们开发了一种称为 DivisionRecorder 的基因追踪方法，它报告了体内细胞库过去增殖的程度。^{使用该系统在病原体特异性免疫反应中以遗传方式“记录”不同 CD8 +} T 细胞群的复制历史，我们证明了中央记忆 T (T _CM) 细胞库的特点是先前分裂次数多于效应记忆 T 细胞库，这是由于急性免疫反应期间的强增殖活性和病原体清除后的选择性增殖活性的结合。此外，通过将 DivisionRecorder 分析与单细胞转录组学和功能实验相结合，我们表明复制历史可识别 T _CM隔室内的不同细胞池。具体来说，我们证明了低分裂的 T _CM细胞表现出丰富的干细胞相关基因表达，以相对静止的状态存在，并且在激活后引发增殖性回忆反应方面表现出色。^{这些数据提供了第一个证据，表明在再感染后重建 CD8 +} T 细胞效应池的干细胞样记忆 T 细胞池以先前的静止为特征。